Genetic Variant SERPINA11:p.Thr369Asn (chr14-94442769-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001080451.2(SERPINA11):c.1106C>A(p.Thr369Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T369S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINA11
NM_001080451.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.12

Publications

0 publications found

Variant links:

Genes affected

SERPINA11 (HGNC:19193): (serpin family A member 11) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SERPINA11 Gene-Disease associations (from GenCC):

hydrops fetalis
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

SERPINA11 links:

ENSG00000256357 (HGNC:):

ENSG00000256357 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080451.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA11	NM_001080451.2	MANE Select	c.1106C>A	p.Thr369Asn	missense	Exon 5 of 5	NP_001073920.1	Q86U17
	SERPINA11	NM_001429948.1		c.494C>A	p.Thr165Asn	missense	Exon 5 of 5	NP_001416877.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA11	ENST00000334708.4	TSL:1 MANE Select	c.1106C>A	p.Thr369Asn	missense	Exon 5 of 5	ENSP00000335024.3	Q86U17
SERPINA11	ENST00000850861.1		c.1115C>A	p.Thr372Asn	missense	Exon 5 of 5	ENSP00000520948.1	A0ABJ7H2Z4
SERPINA11	ENST00000905969.1		c.1106C>A	p.Thr369Asn	missense	Exon 5 of 5	ENSP00000576028.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726386

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111574

Other (OTH)

AF:

0.00

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.1

PhyloP100

7.1

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.75

MutPred

0.71

Loss of phosphorylation at T369 (P = 0.0096)

MVP

0.81

MPC

0.36

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.57

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over